Generation and Function. We propose an integrated program to analyze CD4 and CD8 T cell memory against the respiratory pathogens causing influenza (flu) and tuberculosis (TB). In sophisticated animal models, we will define subsets of CD4 and CD8 memory T cells and determine the cellular and molecular basis of their generation, functions, location, persistence and relationship to other T cell subsets. This will greatly extend our basic understanding of immunity. Generation and Persistence of CD4 Memory Subsets (Swain), will determine the relationships of different functional subsets of CD4 T cells and will determine if they become functionally committed subsets of memory and define their protective functions. They will separate subsets of effector and memory CD4 T cells that work by killing infected targets and compare them to those that cause inflammation and secrete an inflammatory factor IL-17, and those that act by helping B cells. CD8 Memory T Cells Mechanisms of Protection (Dutton) will identify the mechanisms used by the CD8 T cell subsets that parallel those in Project 1 for CD4 subsets. In particular they will study the IL-17 producing subset of CD8 T cells that their preliminary data show plays a key role in protection against influenza, and compare these Tc17 to Tc1 subsets and define their function and protective abilities and mechanisms of action. Regulation Of T Cell Homeostasis and Memory (Bradley), will determine whether signals from selectins expressed on lung cells control CD4 and CD8 T cell responses and are needed for the development and persistence of CD4 memory cells. They will determine if selectin binding capacity identifies a distinct functional subset of CD4 cells, and what CD4 responses are selectin-dependent. T Cell Memory to TB in the Lung (Cooper), will determine factors that regulate induction of protective memory CD4 T cells, especially of the Th17 subset. They will also examine factors in the lung that regulate expression of memory T cell function in the lung and determine whether modulating the IL-17 memory response in the lung can increase protection. Defining the mechanisms by which memory T cell subsets provide protective immunity, is likely to result in identification of new correlates of protection for flu and TB, that will inform future vaccines targeted towards inducing robust T cell memory in addition to antibody, so that immunization will be effective even when new strains of TB and flu, including pandemic flu, emerge.